INTRODUCTION:

Based on their water solubility and membrane permeability, pharmaceutical drugs are divided into four classes by the biopharmaceutics classification system (BCS). Liqui-pellet is a developing dosage form which enhances bioavailability and solubility of the BCS- class II drugs i.e., the drugs having low solubility and high permeability. As the solubility profile of the BCS- class II drugs is low so if, their solubility profile is increased then it leads to the better bioavailability of the drug into body which in turns leads to better therapeutic activity of the drug molecule. Most of the newly invented drug’s molecules lie in the BCS class II or BCS class IV due to their pharmacokinetic properties, lipophilicity and low bioavailability. Physical properties of drugs like water solubility, drug permeability, and dissolution rate influence the bioavailability of the drug molecule and further the efficacy of the pharmaceutical product.

These drugs molecules lack in optimum pharmacokinetics due to their high lipophilicity, less water solubility and high molecular weight when compared to conventional drugs^1–3. To overcome this problem of poor bioavailability many pharmaceutical companies are developing or adopting new technologies to improve solubility profile and bioavailability of the drugs⁴. Methods like salt formation, complexation, co-solvency, micronization, lyophilization, solid dispersion, cyclodextrins, liposomes, nanoparticles, SEDDS (Self-emulsifying drug delivery system), Microemulsions, Self-micro emulsifying drug delivery system (SMEDDS), self-nanoemulsifying drug delivery system (SNEDDS), etc are being used to enhance bioavailability and efficacy of the drugs^5,6.

Liqui-pellet originated by combining liquisolid concept with pelletization technology². The liquisolid system first originated in 90`s. Liquisolid technology is regarded as an innovative technique due to its efficacy, inexpensiveness and potency for industrial production. The liquisolid technique produces tablets and capsules by dispersing or solubilizing a medication in a non-volatile solvent, then mixing the resulting mixture with solid excipients such as carriers and coating materials. Studies on various drugs like spironolactone⁷, valsartan⁸, ritonavir³, felodipine⁹, Naproxen¹⁰, Griseofulvin¹¹, carbamazepine¹², hydrochlorothiazide¹³, glyburide¹⁴, hydrocortisone¹⁵, etc were carried out to improve their dissolution rate by using the liquisolid system⁹.

Liquisolid system:

Liquisolid systems, also referred to as powdered versions of liquid medications, are made by combining liquid lipophilic drugs, drug suspensions, or solutions of water-insoluble solid drugs with specific carrier and coating materials in appropriate non-volatile solvent systems to produce "dry" (i.e., dry-looking), nonadherent, free-flowing, and easily compressible powder admixtures¹⁶. Liquisolid Systems are free flowing, compressible admixtures of drug solutions or suspensions. It is made from the words "liqui," which refers to drug solutions or suspensions, and "solid," which signifies a powdered form. It uses Co-Solvency concept for solubility enhancement of the drug moiety. It is based on the incorporation of a drug that is insoluble in water into a non-volatile solvent in which the drug is relatively soluble, followed by the transformation of the resulting liquid drug solution or suspension into a freely flowing and easily compressible powder using carriers with large specific surface area, porous materials with high liquid absorption capacities, and nanometric sized coating materials with high surface adsorption. Non-volatile liquids like polyethylene glycol, polysorbates, etc which are having high boiling point are mostly preferred as vehicle. Carrier like micro-crystalline cellulose with high absorption capacity and coating material like amorphous silicon dioxide is used which have the high adsorption capacity and fine particle size are used.

Liquid-solid systems appear dry but do not actually contain any moisture since they are molecularly dispersed admixtures of drug solutions or suspensions. These admixtures are compressed into a unit dose form and are known as liquid-solid compacts. The Liquisolid Flowability Test (LSF) and Liquisolid Compressibility Test (LSC), are used to screen the carrier and coating materials' "flowable liquid-retention potential" (Φ) and "compressible liquid-retention potential" (Ψ) values. These variables establish how much liquid drug solution or suspension must be present in order for the carrier and coat to maintain their compressibility and flowability¹.

Fig. 1: Advantages of liquisolid pellets

The liquisolid formulation has significant shortcomings. Due to challenges in achieving uniform feed and reproducible filling for tablet and capsule production, the liquid and powder admixture in particular has poor flow characteristics, which makes the product's creation tough. This resulted in the creation of the Spireas mathematical equation, which is used in order to determine right amount of carrier and coating material in order to utilise and to achieve desired flow properties. The flow characteristics can be increased; by using more carrier and possibly coating material, however, this prevents the liquisolid system from being utilised to deliver high dosages of API because the resulting tablet or capsule would be too big. Additionally, the mixture has low compressibility, which hinders the ability to form a tablet^4,16.

Mechanisms of increased drug release:

For liquisolid systems, a number of methods for improved drug release have been proposed in the literature. Increased drug surface area that is available for release, increased drug solubility, and better wettability of the drug particles are the three major mechanisms proposed.

1. Increased drug surface area: The drug in liquisolid system is still present in powder substrate in a solubilized, molecularly dispersed state even if it has fully dissolved in liquid vehicle. Consequently, compared to drug particles contained in directly compressed tablets, surface area of the drug that is accessible for release is much larger. As a result, release rate reduces when the drug content exceeds the solubility limit and there is a greater proportion of undissolved drug in liquid vehicle. It is possible to demonstrate with a variety of medications that the release rates are directly correlated with amount of molecularly distributed drug (F_M) in the liquid formulation. Spireas et al. describe (F_M) as the ratio of the drug's solubility (S_d) in the liquid vehicle to the actual drug concentration (C_d) in this vehicle that is transported by each system. So,

F_M = S_d/ C_d^15,17,40,49.

2. Increased drug solubility: It is anticipated that liquisolid systems may improve Cs, the drug's solubility. In reality the comparatively little liquid vehicle present in a liquisolid compact is insufficient to significantly improve the drug's overall solubility in the aqueous dissolution medium. However, if the liquid vehicle acts as a co-solvent at the solid-liquid interface between a single liquisolid primary particle and the release medium, the amount of liquid vehicle diffusing out of a single liquisolid particle along with the drug molecules might be sufficient in this microenvironment to increase the solubility of the drug^{15,17,30,40,49}.

Fig. 2, A: Contact angle of conventional tablet B: Contact angle of Liquisolid tablet

3. Improved wetting properties: Wetting of the liquisolid primary particles is enhanced by the liquid vehicle's ability to either function as a surface-active agent or have a low surface tension. Measurement of contact angles and water rising times has been used to show the wettability of these systems. Because liquisolid compacts contain a surface-active agent, they exhibit smaller contact angles than conventional tablets^30,50,51.

Components of Liquisolid System:

1. Non- Volatile solvent: - In order to include the water-insoluble medicine under consideration and ensure that it is easily soluble or suspendable, non-volatile solvents that are water soluble are chosen. They have low viscosity, a high boiling point, and are inert. The final drug solution or suspension need to be safe to ingest. Drug dissolution has been shown to be improved by high liquid concentrations, whilst drug effects are known to be prolonged by low liquid concentrations³⁶. Some Examples are Polyethylene Glycol 200³⁷, Polyethylene Glycol 300¹¹, Polyethylene Glycol 400^10,38, Polyethylene Glycol 600²⁷, Polysorbate 20 (Tween 20)³⁹, Polysorbate 80 (Tween 80)^25,40,41, Propylene Glycol^{12,15,17,25,42}, Glycerin³⁹, Etc.

2. Carrier Material: Carrier material should be added to improve compression. These materials have adequate porosity and soaking potential. As a carrier substance, various forms of cellulose, starch, and lactose are employed. The ability of the carrier material to absorb substances and its drug inertness should be taken into consideration³⁶. Carrier-Porous substances with a large surface area and a high capacity for liquid absorption can be utilised as carriers to take drug solution that results from absorption and turn it into a powder that appears dry and is free to flow. The original carrier for the Liquisolid approach was Microcrystalline cellulose, which was also virtually always utilised in the initial studies on the method. Though over time, many have taken advantage of different carriers in an effort to give the medication a better surface exposure to the dissolving medium. In the end, the quantity of wettability and surface exposure of the drug particles with the dissolution fluid is calculated using powder's Specific Surface Area (SSA). Therefore, choosing a carrier with a large Specific Surface area is crucial¹. Some examples of carrier materials used are Microcrystalline cellulose^{10,12,15,17,38–40}, Ethyl cellulose⁴³, HPMC³⁹, Starch⁴⁴, Lactose^14,33, Mannitol³³, Etc.

3. Coat: Materials are used to seal and coat carrier particles as well as to adsorb any excess liquid. It has very fine particle size and a very adsorptive surface. These adsorptive particles' preferred particle size range is 10nm to 5000nm. Different silica grades are frequently used for coating. Amorphous Silicon Dioxide is commonly used as a coat^{1,10,12,15–17,38–40}. They are primarily used for adsorption behaviour, which makes the material readily flowable. Many people employ amorphous silicon dioxide because it best fits the coat's desired qualities³⁶.

4. Other Excipients: According to the needs, binders, lubricants, diluents, disintegrants, and matrix-forming polymers can be added and blended with the parent preparation. Due to the high concentration of Non-Volatile Solvent in the dry-appearing powder, Super Disintegrants play a crucial function in Liquisolid systems to force open the tablet for disintegration. Without a disintegrant, this may not be possible. It increases release rate of active pharmaceutical ingredient. The Liquisolid Formulations make considerable use of sodium starch glycolate as a super disintegrant^{12,15,17,40,45}. Lubricants can be included, when necessary although they are largely absent from the majority of Liquisolid formulations because the needed flowability is already attained during the precompression phase of the Tablets. Lubricants like Magnesium Carbonate¹³, talc and magnesium stearate⁴³ were used.

Formulation of Liquipellets:

Utilizing both processes the liquid-solid approach followed by extrusion-spheronization is part of the Liquisolid Pellet manufacturing process. Non-volatile solvents should be selected based on the drug's solubility. The goal is to quickly distribute the active components in an inert solvent to produce a liquid pharmaceutical or therapeutic solution. For the purpose of obtaining a clear, homogenous drug solution, this drug solution was sonically processed for 10 to 15 minutes. As a filler and binder for the extrusion-spheronization process, MCC should be combined with a solution or suspension as a carrier.

Fig 3: Summary of Liqui-mass System used to prepare liquid pellet

Cross povidone is added as a coating and dissolving agent at the end, resulting in a moistened powder substance known as a Liquisolid system. After that, solvent is gradually added to the resulting liquid-solid mixture to create appropriate plasticity for extrusion and spheronization. The wet mixture is then quickly extruded through a chosen mesh by an extruder. The resultant extrudates are swiftly transferred to spheronization to produce pellets of high quality. The produced pellets are then dried for 10 to 20 minutes in a fluidised bed drier. To create tablets or fill capsules, the dried pellets are further compressed^2,3,16.

Pellet production using extruder-spheronization:

It involves various steps which are as follows:

I. In order to achieve uniformity in powder dispersion, the processing substance must be fully dried before being mixed.

II. Substance is then wetted to produce an adequate plastic wet load or mass.

III. Extrusion is then applied to the acquired wet mass to create rod-shaped particles.

IV. To produce sphere particles, these rod-shaped particles undergo further spheronization.

V. To obtain the required particle size, the spherical particles are further dried and screened⁴⁶.

Types of extruders: Delivery systems and Die systems are the two main components of extruders. Delivery systems are in charge of moving and mixing the material, whereas die systems aid in shaping the material into the desired form⁴⁷.

On the basis of feed mechanism, extruders are classified as:

1. Screw feed extruder

2. Gravity feed extruder

3. Piston feed or Ram extruder

4. Screen or Basket extruder

5. Roll extruder

Screw feed extruder: Utilize the screw to generate the pressure needed to force the substance to flow. Depending on the design, solids pass through a number of openings, resulting in strands that are similar to each other and are referred to as extrudates. The solid substance was moved from the hopper to the die by means of these devices, which were made up of one or two helical screws rotating in a barrel. The die system, which comes in the shape of an axial or radial screw feeder, consists of a thin steel plate with numerous holes.

Gravity feed extruder: It is composed of moving gear and cylinder, which further merge into roll extruders. They make use of rollers, which places pressure on the substance and produce extrudate. By applying pressure to the wetted material using two rollers, these extruders produced extrudate. The cylinder type extruder has two rollers, one of which is a solid cylinder and the other has a hollow cavity for producing dies. The gear type extruder contains rollers with gear. The third form of extruder is radial, with rotating arms that force wet mass through under pressure. They rip the wet substance and are capable of producing extrudate because there is a rotating blade present.

Ram extruder: The idea behind this kind of extruder is to use a ram or plunger instead of a screw. This extruder uses a piston to move material in the direction of the die at the other end.

Screen or Basket extruder: Extruders of the screen or sieve variety consist of a chamber that holds the material and allows for extrusion. Extrudates that are small or long are created when the substance is forced through a porous screen or sieve in the spinning portion. Moisture is necessary for the creation of these extrudates. The basket extruder is different from the screen extruder in that they are positioned laterally and vertically, respectively.

Roll extruder: It is also referred to as a "pellets mill" and operates by feeding materials between a ring die or plate and roller The roll extruder is designed with a ring die plate rotating inside of a cylindrical die chamber, each rotating on a fixed axis. Every component that can spin is pointing in the same way. The substances are added to the inner surface of the die, and as a result, rollers compress them outside^36,48.

Evaluation Parameters:

· Carr's Index (CI): It is also known as percentage compressibility, is used to evaluate the flowability of all liquisolid formulations and physical combinations. To calculate the CI, the bulk and tapped densities were employed. CI is calculated using the following equation:

(Tapped density – Bulk density)

CI% = --------------------------------------------- ×100

Bulk density

· Hausner Ratio: It is calculated using following formula

Tapped density

Hausner Ratio = -------------------

Bulk density

Table 1: Relation Between CI, Hausner Ratio and Powder Flowability

Carr`s Index	Flow property	Hausner Ratio
≤10	Excellent	1.00-1.11
11-15	Good	1.12-1.18
16-20	Fair	1.19-1.25
21-25	Passable	1.26-1.34
26-31	Poor	1.35-1.45
32-37	Very poor	1.46-1.59
>38	Very very poor	>1.60

· Angle of repose: A glass funnel with a broad mouth was fixed with its tip at a predetermined height above a piece of paper that was placed on a horizontal surface in order to measure the angle of repose. 25g of powder was allowed to slide slowly through tip of the funnel which resulted in the formation of the conical pile of powder. Angle of repose was calculated using following formula:

θ =tan^-1 h/r

Where θ is the angle of repose, and h and r are the height and base radius of the conical pile, respectively¹.

· Determination of the angle of slide (q): It is used for assessing the flow characteristics of powder excipients. The preferred approach to assess the flowability of powders with particles smaller than 150 μm is the angle of slide. On one end of a metal plate with a polished surface, the necessary quantity of carrier is weighed and put in place. Until the plate forms an angle with the horizontal surface where the powder is about to slide, this end is gradually lifted. The sliding angle is the name given to this angle. The ideal flow behaviour for the subsequent processing of liquisolid system admixtures is thought to be a sliding angle of 33° (compressing into tablets, filling into capsules)^52–54.

· Determination of the flowable liquid retention potential (F-value): The ability of a powder material to retain a particular amount of liquid while preserving good flow characteristics is referred to as its flowable liquid retention potential. The maximum mass of a liquid (max) that can be kept per unit mass of the powder material (Q - mass of carrier, q - mass of coating material) in order to produce an acceptable flowing liquid/powder mixture is known as the F-value (FCA - F-value of carrier, FCO - F-value of coating material). The absorption process largely determines the liquid retention potential^{16,50,51,53,55}.

f_CA= m_max/Q

· FTIR: Checks are made to see whether there are any obvious chemical interactions between all of the excipients and liquisolid combinations. The KBr pellet method is frequently used for this, in which the substance under investigation is compressed into a pellet at a ratio of 9:1 to 99:1 as needed, and is compressed under an 8–10 tonne hydraulic press. Additionally, it also revealed that there was no variation in spectra of new and old liquisolid formulations, supporting formulation's stability in high humidity circumstances^7,8.

· Scanning Electron Microscopy: An excellent way to evaluate changes in the microenvironment and potential formulation variations is using SEM experiments. Most studies have noted the disappearance of the drug's crystallinity, with few drug crystals typically being seen for liquisolid formulations. This phenomenon is explained by the carrier's extremely porous structure, which allows for the inclusion and incorporation of the drug, which is a component of a microsystem as a molecular dispersion, rendering the drug visually incomprehensible^1,7,41.

· Particle Size analysis by sieve method: Sieves are used to find out the particle size of all formulations. Pellets were vibrated using a mechanical shaker while being sieved. The pellet yield was calculated using pellet fraction between 250 and 2000μm and is shown as a percentage of total pellet weight².

Liquisolid techniques can be used to enhance the rate of dissolution and boost the solubility of poorly water soluble drugs. Liquisolid techniques can be either used to promote or retard the drug release^56,57

The new technique developed by Spireas ‘liquisolid system’ is the most promising method for improving the dissolution properties of poorly soluble drugs. A liquisolid system (LS) refers to formulations formed by conversion of liquid drugs, drug suspensions or drug solution in non-volatile solvents into dry, non-adherent, free- flowing and compressible powder mixtures by blending with selected carriers and coating materials . Drug present in the liquid medicament in LS is in the solubilized or molecularly dispersed state, so the dissolution can be enhanced by increased surface area and better wetting properties ^58-60The term “liquisolid systems” refers to powdered forms of liquid medications, formulated by converting drug solution of water-insoluble solid drug in suitable non-volatile solvent systems, into “dry” nonadherent, free flowing and readily compressible powder admixtures. The term “liquisolid compact” refers to immediate or sustained release tablet or capsule that are prepared using the technique “liquisolid system”, combined with the inclusion of suitable excipients required for tableting or encapsulation such as disintegrant for immediate release, binder for sustained release action.^61-63“Liquisolid Microsystems”: Refers to capsules prepared by “liquisolid systems” plus the inclusion of an additive resulting in a unit size that may be as much as five times less than that of a liquisolid compact ^64,65

Application of liquisolid technique:

a. Liquisolid technique as a tool to enhance drug dissolution

Low dose insoluble medications like prednisolone¹⁷, famotidine¹⁸, valsartan⁸, ketoprofen¹⁹, raloxifene hydrochloride²⁰, clonazepam²¹, and clofibrate²² have all shown improved dissolving rates thanks to the adoption of the liquid-solid method.

It was shown that the formation of a felodipine liquisolid microenvironment with soft structures and high porosity favoured the process of disintegration and dissolution. The findings suggested that liquisolid pellets could be used as innovative drug delivery devices to improve the rate at which poorly water-soluble medicines dissolve²³.

Liquisolid technology was used to increase the dissolution rate of hydrochlorothiazide in contrast to solid dispersion technique in comparative research to support the viability of the method. The collected data by Khan et al. showed that solid dispersions only boosted the medication dissolving rate to 88% whereas liquisolid systems increased it to 95%. Consequently, it could be concluded that in order to improve the rate and extent of drug release, the liquisolid technique was superior to the solid dispersion technique²⁴.

b. Liquisolid technique as a tool to sustain drug release

In-depth investigations conducted in the last several years suggested that the liquisolid approach could be used as a potential strategy for creating sustained release formulations of many medications. The ability to achieve liquisolid system with zero order release kinetics is one of the key benefits of using the liquisolid technology to delay medication release^25,26.

The basic idea underlying the liquisolid technique is that a sustained release pattern can be created by using hydrophobic carriers (i.e., Eudragit® RL and RS) instead of hydrophilic carriers or retarding agents (such as HPMC) in the liquisolid formulations^28,29. The amount of coating material (such as silica, a hydrophobic material) required to transform wetting carrier particles into seemingly dry and free-flowing powders will also typically be higher because the SSA value of the commonly used hydrophobic carriers (such as Eudragit^® RL and RS) is typically lower than that of the hydrophilic carriers, such as MCC^27,30,31.

c. Liquisolid technique as a tool to minimize the influence of pH variation on drug release

El-Hammadi et al. in his study had used propylene glycol as a liquid vehicle, MCC as a carrier, and silica as a coating material to create a number of liquisolid compositions. In three buffered media with pH values of 1.2, 2.5, and 5, respectively, the dissolving profile of the produced liquisolid tablets was examined. According to the findings, liquisolid tablets dissolve far more quickly and are less sensitive to pH changes than directly compressed and commercially available tablets (Clarityn^®). The findings indicated that the liquisolid approach is a potentially useful tool for reducing the impact of pH change on the rates of drug dissolution for poorly water-soluble medicines ³².

In a different study by Badawy et al., it showed the reliability of mosapride citrate liquisolid tablets, which reduce the impact of pH change on drug release along the gastrointestinal tract with bio-relevant media. Mosapride citrate is a weakly soluble weak base³³.

d. Liquisolid technique as a promising tool to improve drug photostability in solid dosage forms

The photostability research is an essential component of pre-formulation studies for photosensitive pharmaceuticals since a loss of therapeutic potency during the photodegradation process may result in toxic degradation products and cause potential side effects. Silicon dioxide has high refractive index and capacity to diffract light waves of various energies, so it is commonly employed coating material in liquisolid systems and has the photoprotective feature. A number of liquisolid amlodipine formulations were created using Avicel^® PH 102 as the carrier, nanometer-sized amorphous silicon as the coating material, and titanium dioxide either alone or in combination. Amlodipine is a photosensitive medication. The resulting amlodipine liquisolid formulations were exposed to various light doses of visible light, UVA, and UVB for eight hours. The medication alone was also evaluated in the same manner, along with traditional film coating tablets, for comparison. After eight hours of exposure to radiation, it was shown that all liquisolid formulations demonstrated a substantial photoprotective effect, with a residual drug percentage of 97.37% as opposed to 73.8% for the drug alone (P 0.05) ^34,35.

CONCLUSION:

Liquisolid system provides an attractive and easy interface for creating formulations for medications that are poorly soluble in water. Liqui-pellet are most promising dosage form that can be used as a pellet in manufacturing capsules or tablets. The liquipellet possess better bioavailability, better solubility. The liqui-pellets show the following advantages i.e. Improved distribution of drugs, Dose Adjustment, Lower mucosal irritability better drug Dissolution Lower mucosal irritability, Commercial Scale-up. The method of preparation is easy, doesn’t require much efforts. It has been revealed that an improved liqui-tendency pellet's for disintegrating can increase medication release. One could reasonably assume that liqui-pellet is extremely commercially viable without compromising the benefits of liquisolid formulation. In nutshell we can say that liquisolid technology can prove to bring about a paradigm shift in the pharmaceutical market due to its promising approach by enhancing solubility and absorption rates.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

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Received on 02.10.2023 Modified on 07.11.2023

Asian J. Res. Pharm. Sci. 2024; 14(1):63-70.

DOI: 10.52711/2231-5659.2024.00010